Viruses and RNA Interference - CNRS URA 3015  


  HEADDr Maria-Carla SALEH / carla.saleh@pasteur.fr
  MEMBERSDr Maria-Carla Saleh / Dr Bertsy Goic-Figueroa/ Valérie Dorey


  Annual Report

RNAi-mediated viral immunity in insects

The term arbovirus refers to a taxonomically diverse group of mostly RNA viruses that share a similar ecology and maintenance mechanism. The name arbovirus, for arthropod-borne virus , refers to a complex life cycle requiring horizontal transmission by an haematophagous arthropod vector/host between susceptible vertebrate hosts. Although most arboviruses cycle between the insect and small mammals or birds, increasingly frequent crossover events to domesticated animals and humans have resulted in both sporadic epidemics, as well as larger sweeping pandemics.

More than 100 arboviruses cause disease in humans, some of the more common being Western, Eastern and Venezuelan equine encephalitis viruses, Chikungunya virus (alphaviruses); Japanese, St. Louis and Tick-borne encephalitis viruses, Yellow Fever virus, Dengue virus, West Nile virus (flaviviruses); Lacrosse virus, Rift Valley virus (bunyaviruses). Symptomatic infections manifest as headaches, musclepain and high fevers, to more severe complications such as encephalitis, convulsions, paralysis, coma and death. Dengue virus infection alone, for example, results in 100 million cases of febrile illness and 30 thousand deaths per year worldwide.

The economic and health impact of these emerging epidemics has dramatically increased interest into understanding how arboviruses evolve and maintain the ability to cycle between very different hosts. The emphasis of research is now shifting from studying arbovirus infection of human cells, to understanding how the virus behaves within the arthropod vector. Increasing evidence suggests that understanding and controlling the infection in the arthropod before crossover to the mammalian host may be key to combating arboviral infections.

In addition to cell type and tissue specific constraints exerted on the arbovirus by the arthropod host, insects have an active antiviral defense called RNA interference (RNAi) that is able to seek out and destroy viral RNA. The antiviral RNA silencing response of invertebrates is adaptive, potent and rapid; and has features similar to the peptide-based adaptive immunity of mammals. At the whole organism level, RNA silencing may also have the capacity to provide long-term memory, as has been detected in plants; which, after recovering from a virulent primary infection maintain an RNA silencing-mediated resistance to secondary infections.

Studying the antiviral RNAi response in the arthropod, such as in the model organism Drosophila melanogaster, could unravel the mechanisms by which insects harbor virusesand may identify new approaches to control virus replication in the vector, reducing by consequence, transmission events.

Recently we have shown that infected Drosophila cells spread a systemic silencing signal that elicits a protective RNAi-dependent immunity throughout the organism. This suggests that the cell-autonomous RNAi response is insufficient to control a viral infection and that insects also rely on systemic immune response to fight against such infections (Box 1). We have also shown that, in Drosophila, the spread of RNAi is an active process that involves vesicle-mediated intracellular trafficking and depends on lipid modifications and cytoskeleton guidance and that components of the endocytic pathway are required for dsRNA entry to initiate the antiviral RNAi response.

The lab focuses on the molecular and cellular characterization of the dsRNA uptake and spread system. This characterization will lead to a better understanding of the mechanism that mediates the antiviral activity of RNAi in insects.

Keywords: RNA silencing, antiviral RNAi, arboviruses, viral suppressors, drosophila, small RNAs

Via.jpg

Box 1: Model for systemic RNAi viral immunity in Drosophila melanogaster.

Upon viral infection, virus-specific dsRNAs (eg., replication intermediates) are generated during the initial rounds of virus replication. Following cell death or lysis, dsRNAs are taken up and processed by uninfected cells to protect them from subsequent infection, thereby preventing virus spread.



  Publications

van Rij RP, Saleh MC, Berry B, Foo C, Houk A, Antoniewski C, Andino R. (2006) The RNA silencing endonuclease Argonaute 2 mediates specific antiviral immunity in Drosophila melanogaster. Genes Dev. 20:2985-2995

Saleh MC, van Rij RP, Hekele A, Gillis A, Foley E, O'farrell PH, Andino R. (2006) The endocytic pathway mediates cell entry of dsRNA to induce RNAi silencing. Nat Cell Biol. 8(8):793-802. Epub 2006 Jul 23

- Research Highlight article in Nature 442, 332-333 (2006)

- Editor’s Choice in Science 313, 892-893 (2006)

- Research Highlight article in Nature Reviews Mol. Cell. Biol. 7, 630 (2006)

- Faculty of 1000 Biology: Must Read, 6.0 points (August 2006)



  Web Site

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Activity Reports 2009 - Institut Pasteur
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